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Therapeutics Hem/Onc Schober
Exam 2 Antibiotics, Natural Products, Misc
50
Anthropology
3rd Grade
01/25/2011

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Cards

Term
Vinca Alkaloids bind where on the tubulin molecule?
Definition
Beta-subit (site V) near the GTP binding site
Term
Taxanes bind where on the tubulin molecule?
Definition
Bind the beta-subunit (site T)
Term
Epothilones bind where on the tubulin molecule?
Definition
Bind the beta-subunit (site T)
Term
The Vinca Alkaloids include:
Definition
  • Vinblastine
  • Vincristine
  • Vinorelbine
Term
The Taxanes include:
Definition
  • Paclitaxel
  • Docetaxel
Term
Vinca Alkaloids: MOA, Drug Resistance
Definition
  • Bind the beta subunit of the tubulin heterodimer near the GTP binding site
  • Cause shortening (depolymerization) of microtubules -- low concentrations can stabilize microtubule polymers
  • Cell cycle arrest in metaphase -- duplicated chromosomes cannot align properly at division plane
Term
Vinca Alkaloids: Drug Resistance
Definition
  • Drug efflux via P-glycoprotein and the MDRP family
  • Mutations in the beta subunit can decrease drug affinity
Term
Vinca Alkaloids: Toxicity
Definition
  • Neurotoxic symptoms (tingling of extremities, numbness, reduced tendon reflex, motor weakness)
  • Leukopenia (nadir 7-10 days)
  • Inappropriate secretion of ADH (rare)
  • Intrathecal administration FATAL
Term
Paclitaxel: MOA
Definition
  • Binds beta subunit (site T)
  • Stabilizes microtubules, resulting in polymerization
  • Cancer cells arrest in mitosis (metaphase) and enter apoptosis
Term
Docetaxel: MOA
Definition
  • Binds beta subunit (site T)
  • Stabilizes microtubules, resulting in polymerization
  • Cancer cells arrest in mitosis (metaphase) and enter apoptosis
Term
Taxane: Drug Resistance
Definition
  • Drug efflux mechanisms similar to vinca alkaloids
  • Increased anti-apoptosis factors (survivin and aurora kinase)
  • Taxane resistance is p53 independent
Term
Taxanes: Toxicity
Definition
  • Peripheral neuropathy and asthenia is more severe with paclitaxel
  • Paclitaxel --> neutropenia nadir usually occurs 8-11 days after a dose and then reverses by 15-21 days
  • Docetaxel --> more severe, but shorter duration neutropenia
  • Low water solubility requires ethanol or castor oil vehicle administration --> hypersensitivity to vehicle
Term
Ixabepilone: MOA
Definition
  • Binds near taxane site
  • Promotes polymerization
Term
Ixabepilone: Toxicity
Definition
  • Peripheral neuropathy limits treatment
  • Myelosuppression
  • Little cross-resistance with taxanes
Term
Eribulin Mesylate: MOA
Definition
  • Interferes with microtubule polymerization
  • Blocks mitosis
Term
Eribulin Mesylate: Toxicity
Definition
  • Neutropenia
  • Peripheral neuropathy
  • Asthenia
  • QT interval prolongation
Term
The Camptothecins include:
Definition
  • Topotecan
  • Irinotecan
Term
The Epipodophyllotoxins include:
Definition
  • Etoposide
  • Teniposide
Term
Camptothecins: MOA
Definition
  • Binds topoisomerase I
  • Inhibits ligation of DNA strand
  • Apoptosis triggered in S-G2 phase
Term
Camptothecins: Drug Resistance
Definition
  • Drug efflux (P-glycoprotein)
  • Mutations in topoisomerases
Term
Camptothecins: Toxicity
Definition
  • Neutropenia (topotecan > irinotecan)
  • Severe diarrhea (irinotecan > topotecan)
Term
Mechanisms of Diarrhea caused by Irinotecan
Definition
  • Increased unconjugated SN-38 to polymorphisms in UGT
  • Irinotecan inhibits AChE enzyme --> results in increased amounts of ACh, which results in diarrhea
  • Irinotecan affects rapidly turning over cells (such as epithelial cells) which could result in diarrhea
Term
The Anthracycline Antibiotics include:
Definition
  • Daunorubicin
  • Doxorubicin
  • Epirubicin
  • Idarubicin
Term
Anthracycline: MOA
Definition
  • DNA intercalation --> disrupts replication and transcription
  • Binds topoisomerase II and inhibits ligation
  • Drug-DNA interaction generates hydroxyl radicals and hydrogen peroxide which can directly damage (oxidize) DNA bases
Term
Anthracycline: Drug Resistance
Definition
  • Efflux
  • Topoisomerase II mutation
  • Increased DNA repair
Term
Anthracycline: Toxicity
Definition
  • Myelosuppression
  • Cardiotoxicity, through binding of ferrous iron (generates hydroxyl radicals from hydrogen peroxide) and lack of catalase in heart tissue to convert hydrogen peroxide to H2O and O2 --> results in cardiac myocyte damage and heart failure
Term
Dactinomycin: MOA
Definition
  • Intercalates between guanine-cytosine base pair stacks
  • Amino acid side chains insert along the minor groove of DNA forming a very stable drug-DNA interaction
  • Transcription and replication blocked (RNA polymerase more sensitive)
  • Also causes single strand breaks through generation of free radicals and possibly topoisomerase II inhibition
Term
Dactinomycin: Toxicity
Definition
  • Bone marrow suppression
  • Musocal damage
  • Hyperpigmentation of skin (X-ray)
  • Extravasation concern
Term
Bleomycins: MOA
Definition
  • DNA binding
  • Forms complex with ferrous Fe
  • Free radical generation from conversion of ferrous iron to ferric iron which can break glycosidic and phosphodiester bonds
  • Cycle arrest in G2 phase
Term
Bleomycins: Toxicity
Definition
  • Some myelosuppression
  • Pulmonary fibrosis --> may depend on hydrolase which is low in skin andlungs
  • Cutaneous effects (hyperpigmentation, hyperkeratosis, erythema)
Term
Mitomycin: MOA
Definition
  • Requires metabolism for activation of akylation activity of adenine and guanine bases
  • Free radical damage can cause strand breaks
Term
Mitomycin: Toxicity
Definition
  • Myelosuppression
  • Pulmonary fibrosis
  • Hemolytic uremic syndrome
Term
Etoposide: MOA
Definition
  • Binds topoisomerase II
  • Prevents ligation of the double strand cut
  • The cycle stops in S or G2 phase and the tumor cell enters apoptosis
  • Free radical generation may also be important
Term
Teniposide: MOA
Definition
  • Binds topoisomerase II
  • Prevents ligation of the double strand cut
  • The cycle stops in S or G2 phase and the tumor cell enters apoptosis
  • Free radical generation may also be important
Term
Epipodophyllotoxins: Drug Resistance
Definition
  • Expression of drug efflux pumps (P-glycoproteins)
  • Decreased drug binding to topoisomerase
  • Mutation of p53 tumor suppressor gene
Term
Etoposide: Toxicity
Definition
  • Myelosuppression dose limiting
  • GI disturbances
  • Alopecia
  • Risk of toxicity is higher with low serum albumin, such as in hepatic diseases (albumin capacity is saturated so more free drug available)
  • Associated with development of leukemia --> Mixed-Lineage Leukemia gene rearrangement
Term
Teniposide: Toxicity
Definition
  • Myelosuppression dose limiting
  • GI disturbances
  • Alopecia
  • Risk of toxicity is higher with low serum albumin, such as in hepatic diseases (albumin capacity is saturated so more free drug available)
  • Associated with development of leukemia --> Mixed-Lineage Leukemia gene rearrangement
Term
Hydroxyurea: MOA
Definition
  • Inhibits ribonucleotide reductase --> blocks formation of deoxyribonucleotides needed for DNA synthesis
  • Also enhances antimetabolite incorporation (such as cytarabine, fludarabine, and cladribine)
  • Cell arrest near G1-S interface
  • Increases expression of fetal hemoglobin
  • Increases sensitivity to irradiation
Term
Hydroxyurea: Drug Resistance
Definition
Increased production or mutation of hRRM2 subunit of the ribonucleotide reductase enzyme
Term
Hydroxyurea: Toxicity
Definition
  • Leukopenia
  • Megaloblastic anemia (MCV, RDW)
  • Thrombocytopenia
Term
Platinum Complexes: MOA
Definition
  • Enter cell by diffusion or through a copper transporter
  • Crosslinking with two adjacent N7 on guanines of the same strand (intrastrand crosslinking)
  • Adjacent A-G crosslinking also occurs
  • Interstrand crosslinking occurs with much less frequency
  • Drug-DNA adducts interfere with replication and transcription
  • Can trigger apoptosis
Term
Platinum Complexes: Drug Resistance
Definition
  • Intracellular nucleophiles (ie glutathione)
  • Enhanced DNA repair (nucleotide excision)
  • Copper efflux transporter
Term
Cisplatin: Toxicity
Definition
  • Nephrotoxicity dose limiting -- Amifostine can react with and neutralize cisplatin
  • Ototoxicity
Term
Oxaliplatin: Toxicity
Definition
Peripheral neuropathy dose-limiting
Term
Carboplatin: Toxicity
Definition
  • Less ototoxicity, neurotoxicity, and nephrotoxicity --> conversion to reactive (cytotoxic) intermediate is much slower than cisplatin and oxaliplatin
  • Major concern is bone marrow suppression
Term
Thalidomide: MOA
Definition
  • Anti-proliferative effect
  • Blocks adhesion with stromal bone marrow cells
  • Inhibits angiogenesis
  • Enhances natural killer production
Term
Thalidomide: Toxicity
Definition
  • Periperhal sensory neuropathy
  • Severe birth defects
  • Venous thromboembolism in multiple myeloma patients
Term
Bortezomib: MOA
Definition
  • Inhibits proteasome pathway
  • Degradation of target (IkB) protein blocked
  • Gene transcription inhibited of cell survival genes in tumor cells
Term
Bortezomib: ADRs
Definition
  • Thrombocytopenia
  • GI
Term
Vorinostat: MOA
Definition
  • Inhibits histone deacetylases --> favors transcription of genes that regulate cell division, cause cell differentiation, and apoptosis
  • Increases lysine acetylation
  • Activates gene transcription
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